CN102078543A - Traditional Chinese medicine preparation for treating gout and preparation method thereof - Google Patents
Traditional Chinese medicine preparation for treating gout and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of traditional Chinese medicine preparations, and in particular relates to a traditional Chinese medicine for treating gout and a preparation method thereof. The traditional Chinese medicine preparation comprises the following raw materials in parts by weight: 5-40 parts of glabrous greenbrier rhizome, 3-30 parts of rhizoma alismatis, 5-25 parts of root of red rooted salvia, 10-30 parts of rhizoma dioscoreae septemlobae, 1-20 parts of cornel, 1-20 parts of rhubarb, 5-40 parts of celastrus orbiculatus and 1-20 parts of fruit of trifoliate orange. The dosage forms of the traditional Chinese medicine preparation comprise oral solution, tablets, capsules, granules and the like. The traditional Chinese medicine preparation has the efficacies of clearing away heat and promoting diuresis, promoting blood circulation, removing obstruction in channels, decreasing swelling and alleviating pain, and can notably alleviate clinical symptoms of patients with gout, reduce recurrence and reduce the levels of blood uric acid and blood fat and serum creatinine.
Description
Technical field
The invention belongs to field of traditional Chinese, be specifically related to a kind of Chinese medicine that is used for the treatment of gout and preparation method thereof.
Background technology
Gout is to continue the systemic disease that raises and cause owing to heritability or the acquired cause of disease cause purine metabolism obstacle and blood uric acid.Its clinical characters is that hyperuricemia, gouty acute arthritis are shown effect repeatedly.As treat untimely, course of disease delay, gout complication such as hypertension, hyperlipidemia, coronary heart disease, diabetes, renal calculus can occur together.Gout lacks etiological treatment mostly at present, clinical treatment generally to stop the acute arthritis outbreak as early as possible, prevents the arthritis recurrence, corrects hyperuricemia, prevent because of urate deposition in caused complication such as kidney, joints, prevent that the urate calculus formation etc. of kidney from being main purpose.During the acute arthritis outbreak, mainly eliminate the inflammation that urate is brought out, colchicine, nonsteroidal anti-inflammatory drug, and alkalized urine impel the uric acid dissolving to have quick, sure curative effect.In the alleviation of disease and prevent aspect the gout recurrence, allopurinol, upright markon's celestial being, the third sulphur zinc etc. have certain curative effect.Although but the western medical treatment relief of symptoms, toxic and side effects is bigger.The ill situation of China after the eighties in 20th century has gradually ascendant trend, causes many scholars more and more to pay attention to the treatment research of gout, and Chinese medicine, therapy of combining Chinese and Western medicine gout also obtain bigger progress.Chinese medicine gout curative effect certainly.Show from the documents and materials of present various places report, effective percentage is all more than 90%, especially improving patient's symptom and treatment has comparatively remarkable advantages aspect the complication, and toxic and side effects is less, so the Chinese traditional treatment gout has become one of the method that generally adopts and receive treatment clinically, and is rather well received clinically.Yet, clearly be that the Chinese medicine preparation of adaptation disease is still rare with the gout.This problem is intended to develop a kind of gout for the treatment of for adapting to the safe and effective new product of Chinese medicine of disease, meeting clinical needs, and be vast patient with gout releasing suffering of illness, recovers healthy making contributions.
Gout is to continue the disease that raises and cause owing to heritability or the acquired cause of disease cause purine metabolism obstacle and blood uric acid.It is one group of disease of tissue injury due to long-term purine metabolic disturbance, blood uric acid increase.Clinical characters comprise hyperuricemia, gouty acute arthritis show effect repeatedly, treat untimely, course of disease delay, slowly progress, and the gout complication such as hypertension, hyperlipidemia, coronary heart disease, diabetes, renal calculus that can occur together.Modern science thinks that hyperuricemia is the important biochemical basis that gout produces; It is the root that produces hyperuricemia that the Distal convoluted tubule near-end secretion uric acid obstacle of renal tubules and Distal convoluted tubule far-end increase heavily absorbing of uric acid.Because the long-term hyperuricemia that continues, uric acid is saturation in tissue or knuckle synovia, and make positions such as urate crystal is separated out and be deposited on around joint, the joint, subcutaneous and kidney, cause gouty arthritis, tophus, kidney stone or gouty nephropathy etc.The gout main clinical characteristics is that gouty arthritis, gouty nephropathy, tophus and renal calculus form, and normal obesity, hypertension, hyperlipemia, diabetes, arteriosclerosis, coronary heart disease, the cerebrovascular disease etc. of merging.The principle of treatment gout is: logical diet control; Competent moisture is taken in; The daily life system of rule; Suitable sports; Effective Drug therapy; Regular physical examination.The treatment measure comprises: 1. general treatment; 2. the treatment of acute gouty arthritis; 3. the treatment of intermission; 4. the treatment of chronic arthritis phase and tophus; 5. the treatment of gouty nephropathy and urinary system calculus; The disease of 6. treating and depositing.Anti-gout drugs commonly used has colchicine, allopurinol, indometacin, ibuprofen, diclofenac etc.
The traditional Chinese medical science is thought, gout " arthromyodynia " category is waited class mutually with diseases such as " severe and migratory arthralgia ", " severe and migratory arthralgias ".The name of the traditional Chinese medical science " gout " starts from " Further Discourses on the Properties of Things gout ".The traditional Chinese medical science sees " Ling Shu Miraculous Pivot or Divine Axis harmful wind " piece of writing the earliest to the understanding of gout etiology and pathogenesis: " this all tastes and hinders to some extent in dampness, is hidden among the blood vessels, between the boundary between muscles, stays for a long time and does not go, if falling down to some extent, stagnant blood is interior and do not go; The right intemperance of emotions of soldier, diet discomfort, cold temperature frequently, space between skin and muscles closes and obstructed.It is opened and meets wind and cold, and then vim and vigour are condensed, attack mutually with old pathogen, and then be arthralgia due to cold.It has then sweating of heat, and sweating is wind-engaging then.Though do not meet the harmful wind pathogen, must disease on the basis of latent pathogen induced by a new affection be arranged here." " interior warp " point out " so-called numbness person, each is with at that time, reinfection in the wet gas of wind and cold also " again.Zhu Danxi in " Further Discourses on the Properties of Things gout ", point out " gout person, extremity hundred joint is walked pain, the severe and migratory arthralgia wind card of calling in the book is also ... big rate is heated because of blood; from boiling; thereafter or relate to cold water, or upright wetland, or pectinid is got cold; or the wind of working as for sleeping in; fight outside cold and cool, warm blood must be trembled with fear, so dirt is coagulated and puckeryly had a pain, night, then pain was very gone in the moon also." also point out " this is to press blood for oncotic arthralgia of limbs, the hesitant pulse person of number ", " the evil numbness of cold-damp is cloudy divides, and then pain is attacked in heat-transformation for a long time " or the like, cure thereafter family all the ancestor its say.Bright Zhang Jingyue is sayed again in " Jing Yue's complete work migratory arthralgia ": " migratory arthralgia one card, promptly the so-called gout of moderns also "; It thinks in " Jing Yue's complete work beriberi " " outside be that YIN-cold water is wet, modern damp is attacked people's flesh tendon, and is interior by delicious food is excessive usually, the moist chamber part of the body cavity below the umbilicus, housing the bladder, kidneys and bowels is coldly tied strongly fragrant and heat-transformation with damp mutually, stops skin ... diseased region redness hectic fever, for a long time osteomyelitis then ".Zhang Jingyue is classified as migratory arthralgia with gout, and think its onset because of interior by delicious food usually excessively, the wet plug part of the body cavity below the umbilicus, housing the bladder, kidneys and bowels, attack due to people's flesh tendon by damp outward.A clear stone is stupid more to spell out " by gout one card in " the logical gout of Zhang Shi doctor ".The power and prestige of " spirit scratch " meaning, the numbness of " element is asked " meaning, the severe and migratory arthralgia of " goldsmith " name is renamed and say severe and migratory arthralgia later age, how to be attacked in an opponent's defence in meridians by the wind and cold dampness, due to the coagulation of QI-blood ".The good speech of clear analogy is said in " Principle and Prohibition for Medical profession ": " severe and migratory arthralgia wind of gout, arthralgia aggravated by cold also actually ".Clear Lin Peiqin " class disease is controlled sanctions " then says " gout, arthralgia aggravated by cold one disease also ... just divide because of wind and cold damp-stagnancy numbness is cloudy, for a long time then heat-transformation to bitterly, to the Night Watch play "." Elementary Medicine " said: " many endogenous causes of ill blood deficiency has fire for gout, the timid thin person of shape; The fertile brave person of shape, many exopathogenic factors rheumatism is given birth to expectorant; Follow with it and to go through all overly, day severe and migratory arthralgia is very stung as tiger, bitterly must night person very, blood is capable in the moon also ".Gong Tingxian in " ten thousand cause of disease spring ", point out again " all gout limb pain persons, pain belongs to fire, swollen belong to wet ... so people's polyphagia of fat meat and fine grain fry in shallow oil stir-frys, process fight, wine meat, hot thing steams internal organs, so the trouble gout, malignant boil carbuncle person is maximum ".Enumerate the document as can be seen from above-mentioned, ancient medicine has certain approximate part to the etiology and pathogenesis of gout with the modern medicine viewpoint.
Experimentation: Ma Jin etc. summarize the experiment progress of Chinese medicine gout, think that the Chinese traditional treatment method of present gout is more, and all obtain better curative effect.In order to inquire into the therapeutic mechanism of medicine, also more and more to the experimentation of Chinese medicine pain phoenix, can mainly reduce several aspects: anti-inflammatory pain-stopping effect is obvious relatively; Pair cell, the change effect of molecular biology aspect are as the change of norepinephrine (NE), dopamine (DA), 5-hydroxy tryptamine (5-HT) equal size.Pathology aspect research prompting traditional Chinese medical herbal treatment can obviously improve periarticular soft tissues inflammatory cell infiltration, edema, etc., can change rat acute gouty arthritis collagenase activity, alleviate collagen fiber fracture situation.
Damp and hot stasis of blood knot, the turbid malicious stasis of blood of the expectorant stasis of blood hinders, suffer from a deficiency of the kidney etc. all at the common pattern of syndrome of goat, clearing away heat-damp and promoting diuresis, blood circulation and removing stasis, detoxify expel the heat-evil, liver and kidney tonifying etc. is the common method of treatment of goat, and all obtains certain curative effect clinically.
By retrieval, serve as that to adapt to the Chinese patent medicine of disease less clearly with gout, hyperuricemia and complication thereof, mainly contain following kind:
TONGFENGDING capsule: Cortex Phellodendri, Radix Gentianae Macrophyllae, Radix Paeoniae Rubra, Semen Plantaginis etc.Effect: clearing away heat and expelling wind dehumidifying, promoting blood circulation to remove obstruction in the collateral analgesic therapy.Cure mainly the damp-heat syndrome in the numbness disease.Disease is seen the redness and swelling of joints burning pain, with heating, and no relieving of symptom after perspiration, thirst and liking drink, vexed uneasiness, yellow urine, red tongue, yellow and greasy fur, slippery and rapid pulse etc.This product has the effect that reduces blood uric acid, and Western medicine diagnose is that goat meets above-mentioned patient, is suitable for the treatment of this medicine.
XUESHANJINLUOHAN ZHIOTNG TUMOJI: Radix aconiti szechenyiani, Moschus, Stigma Croci, Herba Saussureae Involueratae, Borneolum Syntheticum, Oletum Trogopterori etc.Effect: invigorate blood circulation detumescence, pain relieving.Cure mainly acute and chronic bruise, rheumatic arthritis, gout, scapulohumeral periarthritis, the limbs joint pain and swelling of caused by hyperosteogeny, and neuropathic pain etc.
Gout spirit: mainly form by Radix Cinnamomi Camphorae, Caulis et folium gaultheriae yunnanensis, Acer buergerianum Miq etc.Expelling wind and removing dampness, promoting blood circulation to remove obstruction in the collateral, reducing swelling and alleviating pain.Being used for the treatment of the damp and hot resistance network of gout disease institute to redness and swelling of joints, burning pain, stiff, joint stuffiness, blood uric acid increases etc.
Compound recipe is stretched the muscle capsule: Rhizoma Polygoni Cuspidati, Herba Lycopodii, Radix Parthenocissi Heterophyllae, Radix Cinnamomi Camphorae, Radix Zanthoxyli Spinifolii, Caulis Sargentodoxae, Poria, Rhizoma Alismatis etc.Expelling wind and removing dampness, promoting blood circulation to remove obstruction in the collateral, reducing swelling and alleviating pain.Be used for syndrome of dampness-heat blocking collaterals such as arthromyodynia gout, rheumatoid, rheumatalgia, disease is seen redness and swelling of joints, burning pain, stiff, joint stuffiness etc.
To sum up, mostly the Chinese medicine in the treatment gout medicine is the product of wind-damp dispelling, the meridian dredging, blood circulation promoting and blood stasis dispelling, reducing swelling and alleviating pain; Its treatment pattern of syndrome is also based on damp and hot pattern of syndrome.As seen damp and hot resistance network type gout be clinical in the most common pattern of syndrome; Its Therapeutic Method is also with clearing away heat-damp and promoting diuresis, and promoting blood circulation to remove obstruction in the collateral, reducing swelling and alleviating pain etc. are main.Therefore, continue research and meet the Chinese medicine pharmacology and touch upon and adapt to the disease etiology and pathogenesis, find the Drug therapy of suitable gout to have bigger research and development and be worth.
Summary of the invention
In order to alleviate the patient with gout clinical symptoms and to reduce recurrence, reduce blood uric acid, blood lipid level and serum creatinine, the purpose of this invention is to provide a kind of Chinese medicine preparation for the treatment of gout.
Another object of the present invention provides a kind of method for the treatment of the Chinese medicine preparation of gout.
A kind of Chinese medicine preparation for the treatment of gout of the present invention, the raw material that comprises following weight portion, 5～40 parts of Rhizoma Smilacis Glabraes, 3～30 parts of Rhizoma Alismatis, 5～25 parts of Radix Salviae Miltiorrhizaes, 10～30 parts of Rhizoma Dioscoreae Septemlobaes, 1～20 part of Fructus Corni, 1～20 part of Radix Et Rhizoma Rhei, 5～40 parts of Celastrus orbiculatus Thunb.s, 1～20 part of Fructus Aurantii.
Wherein preferably include the raw material of following weight portion, 8 parts of Rhizoma Smilacis Glabraes, 6 parts of Rhizoma Alismatis, 6 parts of Radix Salviae Miltiorrhizaes, 6 parts of Rhizoma Dioscoreae Septemlobaes, 2 parts of Fructus Corni, 2 parts of Radix Et Rhizoma Rhei, 6 parts of Celastrus orbiculatus Thunb.s, 2 parts of Fructus Aurantiis.
The dosage form of Chinese medicine preparation of the present invention comprises decoction, tablet, capsule and granule, and preferred dosage form is a granule.
Prepare a kind of method for the treatment of the Chinese medicine preparation of gout of the present invention, concrete preparation process is as follows:
1) according to the composition of raw materials proportioning, get Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei of recipe quantity, add 5～7 times of amount 60%～80% ethanol extractions 1～2 hour for the first time, filter; Medicinal residues add 2～5 times of amount 60%～80% ethanol extractions 0.5～1.5 hour again, filter, and filtrate merges, and the relative density that is evaporated to 60 ℃ of heat surveys is 1.05～1.10, and is standby;
2) get all the other 6 flavor medical materials, add Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei medicinal residues after with alcohol extraction, add 8～12 times of water gagings for the first time and extracted 1～2 hour, filter; Add for the second time 6～10 times of water gagings extractions and extracted medical material in 0.5～1.5 hour, filter, filtrate merges, and the relative density that is evaporated to 60 ℃ of heat surveys is 1.05～1.10, and is standby;
3) merge above-mentioned two kinds of concentrated solutions, spray drying, the control inlet temperature is 200～230 ℃, spray speed is 1500～3500ml/h, goes into tower blast 3.0～3.5kg, gets medicine dry powder.
Wherein the concrete steps of preparation method are preferably as follows:
1) according to the composition of raw materials proportioning, get Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei of recipe quantity, add 7 times of amount 80% ethanol extractions 2 hours for the first time, filter; Medicinal residues add 5 times of amount 80% ethanol extractions 0.5 hour again, filter, and filtrate merges, and the relative density that is evaporated to 60 ℃ of heat surveys is 1.05～1.10, and is standby;
2) get all the other 6 flavor medical materials, add Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei medicinal residues after with alcohol extraction, add 12 times of water gagings for the first time and extracted 2 hours, filter; Add for the second time 10 times of water gagings extractions and extracted medical material in 1.5 hours, filter, filtrate merges, and the relative density that is evaporated to 60 ℃ of heat surveys is 1.05～1.10, and is standby;
3) merge above-mentioned two kinds of concentrated solutions, spray drying, the control inlet temperature is 220 ℃, spray speed is 3500ml/h, goes into tower blast 3.0～3.5kg, gets medicine dry powder.
After making medicine dry powder, with the dry powder of 10 weight portions and the dextrin mix homogeneously of 0.25～2 weight portion, 80%～98% alcohol granulation, drying, granulate, packing gets granular preparation.
Chinese medicine preparation of the present invention is promptly abided by the method prescription and is selected medicine and form.The Rhizoma Smilacis Glabrae slightly sweet flavor is flat, goes into liver stomach two warps, has clearing away heat-damp and promoting diuresis, lets out turbid diuresis.As Compendium of Material Medica speech " dampness removing reduces phlegm and internal heat, and can go into network, searches and picks the damp and hot poison that accumulates ".Radix Salviae Miltiorrhizae bitter in the mouth cold nature is gone into the heart, Liver Channel, has blood circulation and removing stasis, the detoxifcation effect of expelling the heat-evil, " be apt to control blood system, remove the tissue regeneration promoting that stagnates, regulating menstruation along the feeling pulse medicine also ".Above two medicines of we are shared to be monarch, with clearing away heat-damp and promoting diuresis, and promoting blood circulation to remove obstruction in the collateral.Square with Rhizoma Alismatis, Rhizoma Dioscoreae Septemlobae, Radix Et Rhizoma Rhei, Pseudobulbus Cremastrae Seu Pleiones, Fructus Aurantii are ministerial drug.The Rhizoma Alismatis sweet in the mouth is cold in nature, goes into kidney, urinary bladder channel, has the eliminating dampness and diuresis effect, and the mixed soil Poria more helps clearing away heat-damp and promoting diuresis.The Rhizoma Dioscoreae Septemlobae bitter in the mouth is flat, goes into liver, kidney, urinary bladder channel, and the tool dampness removing is let out turbid merit, further assists the Rhizoma Smilacis Glabrae removing dampness and detoxicating, and easing joint movement.The Radix Et Rhizoma Rhei bitter in the mouth is cold in nature, goes into spleen, stomach, large intestine and Liver Channel, has removing blood stasis and invigorates blood circulation, and turbid effect is rushed down in heat clearing away, cooperates the Radix Salviae Miltiorrhizae blood circulation and removing stasis, and can purge heat.Consumption is few in the side, keeps away its bitter cold, captures the effect of gushing.Pseudobulbus Cremastrae Seu Pleiones sweet in the mouth little suffering of a specified duration is cold, goes into liver stomach two warps, has heat-clearing and toxic substances removing, the mass dissipating and swelling eliminating effect, and can assist to separate turbid poison.With the acid temperature of the sweet in the mouth of Fructus Corni, go into liver, kidney two warps, the tool liver and kidney tonifying is restrained back puckery merit.It can nourishing YIN, again can YANG invigorating, and both mended and held back, the key medicine of the treating the liver kidney deficiency that does good, thus be adjuvant drug with it, to take into account Liver and kidney.Fructus Aurantii bitter in the mouth acidity is slightly cold, and goes into taste two warps, separates dispelling the stagnated QI, removing food stagnancy, reduces phlegm, and therapeutic method to keep the adverse QI flowing downwards relieving constipation makes gas freely then help with humidifying ruton.
In sum, Chinese medicine preparation of the present invention has the merit of clearing away heat-damp and promoting diuresis, promoting blood circulation to remove obstruction in the collateral, reducing swelling and alleviating pain, with damp-heat congestion type goat stapler machine due to illness, when proving effective, is applicable to the damp and hot silt resistance type gout of treatment, hyperuricemia.We take into account it to take stopgap measures, and medication also has certain characteristic.
The specific embodiment
[prescription]
Radix Salviae Miltiorrhizae 750g
Rhizoma Smilacis Glabrae 1000g
Rhizoma Alismatis 750g
Celastrus orbiculatus Thunb. 750g
Fructus Corni 250g
Radix Et Rhizoma Rhei 250g
Fructus Aurantii 250g
Rhizoma Dioscoreae Septemlobae 750g
Dextrin is an amount of
Make the 1000g granule
[method for making]
More than 8 flavors, get Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei of recipe quantity, add 7 times of amount 80% ethanol extractions 1.0 hours for the first time, filter; Medicinal residues add 5 times of amount 80% ethanol extractions 0.5 hour again, filter, and filtrate merges, and are evaporated to relative density and are 1.05～1.10 (60 ℃ of heat are surveyed), and are standby.
Get all the other 6 flavor medical materials, add Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei medicinal residues after with alcohol extraction, add 12 times of water gagings for the first time and extracted 2 hours, filter; Add for the second time 10 times of water gagings extractions and got and medical material in 1.5 hours, filter, filtrate merges, and is evaporated to relative density and is 1.05～1.10 (60 ℃ of heat are surveyed), and is standby.
Merge above-mentioned two kinds of concentrated solutions, spray drying, the control inlet temperature is 210～220 ℃, spray speed is 3500ml/h, goes into tower blast 3.0～3.5kg, gets medicine dry powder.With spray drying gained dry powder and an amount of dextrin mix homogeneously, 90% alcohol granulation, drying, granulate, packing, promptly.
[Study on extraction]
One, the evaluation of raw material and check
Salvia piece:, be dry root and the rhizome of labiate Radix Salviae Miltiorrhizae (Salvia miltiorrhiza Bge.) available from Changsha three Hunan medical material companies.Meet requirement under Radix Salviae Miltiorrhizae item of Pharmacopoeia of the People's Republic of China version in 2000 through check.Rhizoma Smilacis Glabrae decoction pieces:, be the dry rhizome of liliaceous plant light leaf greenbrier Carve Smilax glabra Roxb. available from Changsha three Hunan medical material companies.Meet " requirement under Rhizoma Smilacis Glabrae item of Chinese pharmacopoeia version in 2000 through check.
The Rhizoma Alismatis decoction pieces: available from Changsha three Hunan medical material companies, be the dry tuber of Alismataceae plant Rhizoma Alismatis Alisma orientalis (Sam.) Juzep..Meet requirement under Rhizoma Alismatis item of Pharmacopoeia of the People's Republic of China version in 2000 through check.
Rhizoma Dioscoreae Septemlobae decoction pieces:, be the dry rhizome of Dioscoreaceae plant Rhizoma Dioscoreae Septemlobae Dioscorea septemlobaThunb. available from Changsha three Hunan medical material companies.Meet requirement under Rhizoma Dioscoreae Septemlobae item of Pharmacopoeia of the People's Republic of China version in 2000 through check.Fructus Aurantii decoction pieces:, be the dry immature fruit of rutaceae Citrus aurantium Linn. Citrus aurantium L. available from Changsha three Hunan medical material companies.Meet requirement under Fructus Aurantii item of Pharmacopoeia of the People's Republic of China version in 2000 through check.Radix Et Rhizoma Rhei decoction pieces:, be dry root and the rhizome of Polygonaceae Rheum officinale Rheum officinale Baill. available from Changsha three Hunan medical material companies.Meet requirement under Radix Et Rhizoma Rhei item of Pharmacopoeia of the People's Republic of China version in 2000 through check.Celastrus orbiculatus Thunb. decoction pieces:, be the dry rattan of Wei Maoke plant Celastrus orbiculatus Thunb. Celatrus orbiculatusThumberg and the dry pseudobulb of root available from Changsha three Hunan medical material companies.Meet requirement under Celastrus orbiculatus Thunb. item of " Hunan Province's medical material standard " version in 2009 through check.
Fructus Corni decoction pieces:, be the drying and ripening sarcocarp of Cornaceae plant Fructus Corni Cornus officinalisSieb.et Zucc. available from Changsha three Hunan medical material companies.Meet requirement under Fructus Corni item of Pharmacopoeia of the People's Republic of China version in 2000 through check.
Above raw material is through the clean system of medical material company processing, and preparation prescription do not have special process of preparing Chinese medicine requirement to raw material, directly selects the decoction pieces of purchasing for use so this is studied.
Two, the design of extraction process route
Chinese medicine preparation agent prescription of the present invention is from noble and unsullied scientific research screening side of giving birth to professor.By Rhizoma Smilacis Glabrae, Radix Salviae Miltiorrhizae, Rhizoma Alismatis ， Rhizoma Dioscoreae Septemlobae, Radix Et Rhizoma Rhei, Celastrus orbiculatus Thunb., Fructus Aurantii, Fructus Corni is formed.Effect with promoting blood circulation to remove obstruction in the collateral, clearing away heat-damp and promoting diuresis and reducing swelling and alleviating pain.Be mainly used in treatment damp-heat congestion type gout, hyperuricemia.We are according to the contained effective ingredient of different flavour of a drug and physicochemical property thereof, pharmacological action in the prescription, and need and the result of our trial test with reference to relevant documents and materials, clinical requirement, preparation, and eight medicines of distinguishing the flavor of are divided into following a few part and carry out different disposal in general the side:
1. Rhizoma Smilacis Glabrae sweet in the mouth, light, property are flat, return liver, stomach warp, detoxifcation are arranged, dehumidifying, effects such as sharp joint.Be used for the treatment of diseases such as syphilis, stranguria with turbid discharge, beriberi, treatment skin ulcer, carbuncle, pestilence.Main chemical compositions has: saponin, tannin, resin etc.These compositions are all water-soluble, so use water extraction, also meet the traditional extraction process that Rhizoma Smilacis Glabrae is gone into decoction.
2. Radix Salviae Miltiorrhizae has blood circulation and removing stasis, the detoxifcation effect of expelling the heat-evil.Main effective ingredient is a Tanshinone I, Tanshinone I I
A, liposoluble constituent and danshensus such as cryptotanshinone, saivianic acid A, second, the third, protocatechuic acid, water soluble ingredients such as protocatechualdehyde.Shared with Rhizoma Smilacis Glabrae in we is monarch drug, with clearing away heat-damp and promoting diuresis, and promoting blood circulation to remove obstruction in the collateral.Modern study proof Tanshinone I I
AAlmost insoluble in water Deng liposoluble constituent, so consider Radix Salviae Miltiorrhizae is used earlier the ethanol extraction of debita spissitudo, the medicinal residues water is carried then.
3. Rhizoma Alismatis is cold in nature, and sweet in the mouth, light is returned kidney, urinary bladder channel.The effect that have promoting diuresis to eliminate damp pathogen, expels the heat-evil.Be used for dysuria, edema distension, have loose bowels, disease such as oliguria, phlegm retention, dizzy, puckery pain of pyretic stranguria.Key medicine for promoting diuresis to eliminate damp pathogen.Its alisol constituents Alisol A acetas, alisol B acetas etc. have diuresis, blood fat reducing, anti-fatty liver and hepatoprotective effect, main active for Rhizoma Alismatis, the discharge that healthy human oral Rhizoma Alismatis decoct can be seen urine amount, sodium and carbamide increases, Rhizoma Alismatis water decoction 20g/kg has antiobesity action to the obese rat that sodium glutamate causes, can reduce fat index and serum levels of triglyceride content around Lee exponential quantity, uterus and the testis of obese rat.So use water extraction.
4. Rhizoma Dioscoreae Septemlobae has dampness removing and goes turbidly, and the effect of the blood stasis dispelling that dispels the wind is used for gonorrhea nebulousurine, leukorrhagia, herpes simplex pain, waist knee joint arthralgia pain.The master contains dioscin, so available water is carried.
5. Celastrus orbiculatus Thunb. has activating blood and removing stasis, expelling wind and removing dampness, is used for traumatic injury, bones and muscles pain, numb limbs and tense tendons, amenorrhea paralysis.
6. Radix Et Rhizoma Rhei has purging heat and dredging bowels, removing pathogenic heat from blood and toxic substance from the body, the effect of eliminating blood stasis and inducing menstruation.Main component has the anthraquinone class, stilbene glycoside, chromone class, naphthols glycoside, phenyl propyl ketone class and tannin class.The main Radix Salviae Miltiorrhizae removing blood stasis that cooperates is invigorated blood circulation in we, and purges heat.Modern pharmacological research proof rhubarb anthraquinone has and rushes down down blood pressure lowering, the effect of invigorating blood circulation.Relevant bibliographical information is an index with the total Radix Et Rhizoma Rhei anthraquinone, and alcohol reflux technology is better than percolation and extraction process by water.Consider that again the anthraquinone class is dissolved in alcohol, water, be the thermal instability material, in the traditional water decoct under the suitable back.In order to protect thermal instability material such as anthraquinone class and conveniently to use in big production, so at first Radix Et Rhizoma Rhei and Radix Salviae Miltiorrhizae one used the ethanol extraction of debita spissitudo, the medicinal residues water is carried then.
7. Fructus Aurantii, cold nature, bitter in the mouth, suffering, acid.Go into lung, spleen, large intestine channel.Has regulating the flow of QI to ease the stomach, the effect of the stagnant relieving distension of row.Cure mainly in stagnation of circulation of vital energy about brestribs, distension pain, accumulation of food in the stomach and intes tine due to indigestion, the phlegm retention stop, gastroptosis etc.Contain materials such as flavonoid glycoside, alkaloids, coumarin, tannin, saccharide and organic acid.These compositions have certain dissolubility in water, so use water extraction.
8. Fructus Corni sour in the mouth, puckery, tepor is returned liver, kidney channel.Its effect is a liver and kidney tonifying, essence astringing and desertion stemming.The clinical interior-heat that is used for is quenched one's thirst, vertigo and tinnitus, soreness of waist and knee joint, impotence and seminal emission, urine enuresis frequency, bleeding not during menses, profuse sweating collapse etc.In we, be adjuvant drug, take into account Liver and kidney.Lead glycoside such as containing cornin, morroniside and tannin, organic acid.These compositions are all water-soluble, so use water extraction, also meet the traditional extraction process that Fructus Corni is gone into decoction.
But because this side was decoction originally, and effective ingredient is indeterminate, thus Radix Salviae Miltiorrhizae, the first ethanol extraction of using of Radix Et Rhizoma Rhei, the medicinal residues after the extraction again with other medicinal water extraction.
Three, Study on extraction
(1) Radix Salviae Miltiorrhizae, Radix Et Rhizoma Rhei ethanol extraction technical study
Consider the number of times that mainly contains concentration of alcohol, extraction, the extraction time that may influence the ethanol extraction effect, four factors such as alcohol adding amount, according to experience in the past, earlier extraction time is investigated separately, and then according to the result, adopting orthogonal experiment, serves as that the examination index is examined or check with the extraction ratio and the yield of extract of TANSHINONES, the optimum process technology condition that preferred Radix Salviae Miltiorrhizae, Radix Et Rhizoma Rhei extract.
1 extraction time is determined
Get Radix Salviae Miltiorrhizae 75g, Radix Et Rhizoma Rhei 25g, add 70% ethanol extraction 3 times, be respectively 8 times, 6 times, 6 times amounts, extraction time was respectively 2 hours, 1 hour, 1 hour, collected each extracting solution respectively, was concentrated into 500ml, and is standby.
Determination of extractives: get above-mentioned each 25ml of solution that extract for 3 times respectively in the evaporating dish of constant weight, water bath method moves in the baking box 105 ℃ of bakings 4 hours, moves in the exsiccator and cools off, and weighs, and calculates yield of extract respectively by following formula, the results are shown in Table 1.
Dried cream yield=dried cream weight/crude drug amount * 100%
TANSHINONES assay: adopt the HPLC method.
Chromatographic condition: immobile phase: octadecylsilane chemically bonded silica; Mobile phase: methanol-water (85: 15); Detect wavelength: 270nm; Column temperature: 35 ℃; Flow velocity: 1.0ml/min.
Sample solution preparation: get extracting solution 1ml for the first time respectively, extracting solution 5ml for the second time, extracting solution 10ml for the third time, water bath method, residue is with dissolve with methanol and be settled to 10ml, for measuring TANSHINONES content.
Sample determination: with above-mentioned sample solution sample introduction 5ul, the record peak area is pressed standard curve and is calculated TANSHINONES content, is calculated as follows the rate of transform, the results are shown in Table 1.(TANSHINONES content is 3.68% in this batch Radix Salviae Miltiorrhizae)
The content of TANSHINONES in the rate of transform=medicinal liquid of TANSHINONES/(TANSHINONES content in Radix Salviae Miltiorrhizae crude drug amount * red rooted salvia) * 100%
Table 1 extraction time is investigated the result
* refer to that the single extraction accounts for the percentage ratio of total extraction
As can be seen from Table 1, the dry extract yield that preceding second extraction merges and the TANSHINONES rate of transform account for extract for three times merge more than 90%, that extracts for the third time only accounts for less than 10%, so Radix Salviae Miltiorrhizae, Radix Et Rhizoma Rhei orthogonal test alcohol extraction number of times employing secondary.
The preferred Radix Salviae Miltiorrhizae of 2 orthogonal tests, Radix Et Rhizoma Rhei extraction conditions
With concentration of alcohol, extraction time, adding amount of alcohol is the investigation factor, uses L
9(3
4) the orthogonal table experiment arrangement, be evaluation index with the extraction ratio and the yield of extract of TANSHINONES.According to prerun, draft investigation factor and water-glass and see Table 2, orthogonal test scheme and the results are shown in Table 3.Variance analysis as a result sees Table 4, table 5.
Table 2 Radix Salviae Miltiorrhizae, Radix Et Rhizoma Rhei extraction process factor level table
Experimental technique and result: take by weighing red rooted salvia 60g, rhubarb medicinal material 20g, according to the orthogonal table experiment arrangement, merge secondary raffinate, concentrate, be settled to 500ml, the above-mentioned solution 4ml of accurate absorption, put evaporate to dryness in the evaporating dish, add the dissolve with methanol standardize solution, shake up in the 10ml measuring bottle, filter with microporous filter membrane (0.45um), filtrate is as test liquid.Measure extractum yield and TANSHINONES content as stated above respectively, calculate the yield of extract and the rate of transform.
Design of table 3 alcohol extraction process orthogonal experiment and result
Table 4 is analysis of variance table (yield of extract) as a result
Look into F-distribution tables of critical values: F
0.05(2，2)＝19.00 F
0。01(2，2)＝99.00
Table 5 is analysis of variance table (TANSHINONES extraction ratio) as a result
From The results of analysis of variance as can be known: for yield of extract, A factor significant difference (P＜0.05), A in the A factor
1＞A
2＞A
3, optimum level A
1C factor significant difference (P＜0.05), C in the C factor
3＞C
2＞C
1, optimum level C
3B factor difference is not significantly (P＞0.05) all, can and consider B and A according to the principle of saving energy consumption
1, C
3Collocation select, so with A
1B
2C
3Be combined as good.For the TANSHINONES extraction ratio, A factor significant difference (P＞0.05), A in the A factor
3＞A
2＞A
1, optimum level A
3All not remarkable (P＞0.05) the extreme difference R of B, C factor difference
B＞R
CSo the secondary factors that influences experimental result is A＞B＞C in proper order; B in the B factor
3＞B
2＞B
1, the B factor is got B
3Level, difference is little in the C factor, according to the principle of saving energy consumption, selects C
1Level.So with A
3B
3C
1Be combined as good.
Demonstration test: because preferred technology is not included in 9 tests of orthogonal array, so it has been carried out demonstration test.With with a collection of medical material, take by weighing 1/5 recipe quantity, press A respectively
1B
2C
3, A
3B
3C
1Compare test, measure yield of extract and TANSHINONES extraction ratio, the results are shown in Table 6.
Table 6 demonstration test result
By table 6 as seen, be index with the yield of extract, A
1B
2C
3Be better than A
3B
3C
1, be index with the TANSHINONES extraction ratio, A
3B
3C
1Be better than A
1B
2C
3As seen determining alcohol is high more, and the TANSHINONES extraction ratio is high more, and yield of extract is lower.But since Radix Salviae Miltiorrhizae, Radix Et Rhizoma Rhei with ethanol extraction after, medicinal residues will be again with other medicine water extraction, so definite ethanol extraction process conditions are A
3B
3C
1, promptly add for the first time 7 times of amount 80% ethanol extractions 1 hour, add 5 times of amount 80% ethanol extractions 0.5 hour for the second time.
(2) medical material extraction process by water such as Fructus Aurantii research
1. measuring naringin content in the Fructus Aurantii medical material
Get Fructus Aurantii coarse powder 0.2 gram, the smart title,, add 50ml methanol, backflow 1.5h gets filtrate 4ml, and the evaporate to dryness measuring naringin content shifts with methanol, and standardize solution is in 10ml.Recording naringin content by following method for measuring naringin content is 6.75%.
2. the research of water extraction number of times
Except that Radix Salviae Miltiorrhizae, Radix Et Rhizoma Rhei, take by weighing the medical material of recipe quantity 1/50, add Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei medicinal residues (following orthogonal test is method herewith) that extracted with the optimum process technology condition in the prescription ratio, water decocts 3 (the 1st 12 times of water 1.5h, the 2nd 10 times of water 1.0h, the 3rd 10 times of water 1.0h), filter, collect filtrate respectively.The 1st fry in shallow oil, the 2nd fry in shallow oil, the 3rd fry in shallow oil to concentrate and be settled to 500ml, standby.
Determination of extractives: get above-mentioned each 25ml of solution that extract for 3 times respectively in the evaporating dish of constant weight, water bath method moves in the baking box 105 ℃ of bakings 4 hours, moves in the exsiccator and cools off, and weighs, and calculates yield of extract respectively by following formula, the results are shown in Table 7.
Dried cream yield=dried cream weight/crude drug amount * 100%
Measuring naringin content: adopt the HPLC method.
Chromatographic condition: immobile phase: octadecylsilane chemically bonded silica; Mobile phase: methanol-water-0.05% phosphoric acid (45: 45: 10);
Detect wavelength: 283nm; Column temperature: 35 ℃; Flow velocity: 1.0ml/min.
Sample solution preparation: get extracting solution 2ml for the first time respectively, extracting solution 5ml for the second time, extracting solution 10ml for the third time, water bath method, residue is with dissolve with methanol and be settled to 10ml, for measuring naringin content.
Sample determination: with above-mentioned sample solution sample introduction 5ul, the record peak area is pressed standard curve and is calculated naringin content, is calculated as follows the rate of transform, the results are shown in Table 7.
The content of naringin in the rate of transform=medicinal liquid of naringin/(naringin content in Fructus Aurantii crude drug amount * Fructus Aurantii medical material) * 100%
Table 7 extraction time is investigated the result
* refer to that the single extraction accounts for the percentage ratio of total extraction
As can be seen from Table 7, the dry extract yield that preceding second extraction merges and the naringin rate of transform account for three times and extract more than 90% of merging, and that extracts for the third time only accounts for less than 10%, and Gu Zhengjiaoshiyanshui carries number of times and adopts secondary.
3. water is put forward orthogonal test
With soak time, amount of water, extraction time be the investigation factor, use L
9(3
4) the orthogonal table experiment arrangement, be evaluation index with the extraction ratio of naringin and extractum.According to prerun, draft investigation factor and water-glass and see Table 8, orthogonal test scheme and the results are shown in Table 9.Variance analysis as a result sees Table 10, table 11.
Table 8 extraction process by water factor level table
Experimental technique and result: the method by the research of water extraction number of times takes by weighing medical material, according to the orthogonal table experiment arrangement, merge secondary raffinate, be settled to 500ml after concentrating, the above-mentioned solution 5ml of accurate absorption puts evaporate to dryness in the evaporating dish, add the dissolve with methanol standardize solution in the 10ml measuring bottle, shake up, filter with microporous filter membrane (0.45um), filtrate is as test liquid.Measure extractum yield and naringin content as stated above respectively, calculate the yield of extract and the rate of transform.
Design of table 9 extraction process by water orthogonal experiment and result
Table 10 is analysis of variance table (yield of extract) as a result
Look into F-distribution tables of critical values: F
0.05(2，2)＝19.00 F
0。01(2，2)＝99.00
Table 11 is analysis of variance table (the naringin rate of transform) as a result
From The results of analysis of variance as can be known: for yield of extract, C factor significant difference (P＜0.05), C in the C factor
3＞C
2＞C
1, optimum level C
3A, B factor zero difference (P＞0.05) can according to circumstances be arranged in pairs or groups arbitrarily with other factors, for the naringin rate of transform, and B factor significant difference (P＜0.05), B
3＞B
2＞B
1, the B factor is got B
3Level; A, C factor are secondary cause (P＞0.05), can according to circumstances arrange in pairs or groups arbitrarily with other factors.Take all factors into consideration the yield of extract and the naringin rate of transform, so can determine earlier that B, C experimental program are B
3C
3The A factor is a secondary cause, in order to save the production time; So determine A
1B
3C
3Be combined as optimised process.Be that medical material does not soak, add 12 times of water gagings for the first time and extracted 2 hours, add 10 times of water gagings for the second time and extracted 1.5 hours.
Because the preferred technology of institute is in the scheme of Orthogonal Experiment and Design (No. 3 test), so it has not been carried out demonstration test.
[concentration technology research]
In order to reduce the exsiccant temperature of solution concentration and thick paste, prevent the destruction of effective ingredient, the destruction of thermal sensitivity composition particularly, improve concentrated, exsiccant efficient, we are index with TANSHINONES and product form, adopt (60～70 ℃ of concentrating under reduced pressure, 0.06～0.07mPa vacuum), spray drying, normal pressure concentrates, the constant pressure and dry method has prepared product respectively and compared, and the results are shown in Table 12.(TANSHINONES assay and rate of transform computational methods are seen the method under the extraction process item)
The different product form and the TANSHINONES rates of transform that reach under the drying condition that concentrate of table 12
The result shows, the product TANSHINONES rate of transform height of concentrating under reduced pressure, spray drying process preparation, of light color, be not stained with tank skin, dissolubility is good, and concentrating under reduced pressure is described, spray drying process is better than additive method, so the aqueous solution and the thick paste of this prepared all adopt concentrating under reduced pressure, spray-dired method concentrates and is dry.
[selection of spray drying condition]
Adopt conventional way to dry and even with the way drying that reduces pressure, all be not easy to do, gained extractum is hard, and is easy to coking, and spray drying method can reduce the material heated time, and has avoided above shortcoming, so select to carry out drying with spray drying method.The factor that influences spray-drying process has extractum density, inlet temperature, spray speed, goes into the tower blast, so it is investigated.
(1) extractum density determines
Spray drying effect and extractum density have very confidential relation.In trial test, find the too big easily sticking blocking sprayer of density, and spraying granule is big, cause extractum drying rapidly, in bulk also can bond; Density is too little, and the solid content of extractum is low, makes spray drying time lengthening, and energy consumption increases, and is index with the medicated powder form and the amount of collecting medicated powder in the unit interval therefore, and preferred extractum density the results are shown in Table 13.
Table 13 extractum density is to the result of spray drying influence
As can be known from Table 13, the amount of collecting medicated powder in relative density 1.11-1.12 (the 60 ℃ of surveys) unit interval is many, but concentration time is longer, and the sticking wall of powder, influences subsequent treatment, and during relative density 1.02-1.04 (60 ℃ of surveys), the spray drying time is longer.And when relative density was 1.05-1.10 (the 60 ℃ of surveys) left and right sides, spray-dired effect was better.Therefore in spray drying, the relative density of determining extractum is 1.05-1.10 (60 ℃ of survey).
(2) inlet temperature determines
The inlet temperature height, the effective ingredient destructible of extractum, and possibility gelatinizing, the dry powder water content is low more, and the too low extract dry of temperature is incomplete, process is long slightly, easily caking.Through prerun, be index with the moisture in dry powder color and luster, the dry powder and the TANSHINONES rate of transform, fix other conditions, inlet temperature is carried out preferably the results are shown in Table 14.
Table 14 inlet temperature is to the result of spray drying influence
As can be known from Table 14,210～220 ℃ of inlet temperatures, spray-dired effect is more satisfied.
(3) determining of spray speed
Spray speed is high more, and the dry powder water content is big more; Otherwise spray speed is low more, and the dry powder water content is more little, but spray time is long, and production cost increases.Through prerun, be index with moisture in dry powder color and luster, the dry powder, fix other conditions, carry out preferably the results are shown in Table 15 to spraying speed.
Table 15 spray speed is to the result of spray drying influence
As can be known from Table 15,210～220 ℃ of inlet temperatures, spray-dired effect is more satisfied.
(4) go into determining of tower blast
Compressed air pressure also produces certain influence to the spray drying result, and pressure is more little, and dry powder is thick more, difficult more granulation; Otherwise pressure is big more, and dry powder is thin more, easy more granulation, but pressure is excessive, then can damage nebulizer, so the size of going into the tower blast is investigated, rule of thumb reaches test of many times, determines to be controlled at 3.0～3.5kg into the tower blast.
Take all factors into consideration every factor, select best drying process with atomizing according to the experimental result finishing screen: about extractum relative density 1.05-1.10, inlet temperature is 220～210 ℃, and spray speed is 3500ml/h, and going into the tower blast is 3.0～3.5kg.
[preparations shaping research]
(1) the selection foundation of dosage form
We through the hundreds of routine patients of clinical use, have satisfactory therapeutic effects according to noble and unsullied scientific research screening side of giving birth to professor, especially comparatively remarkable advantages are arranged aspect patient's symptom improving.Though we's decoction has satisfactory therapeutic effects, the patient takes inconvenience, and is especially should side's flavour of a drug more, adheres to that treatment brings difficulty for the patient that goes out.Therefore need be prepared into storage, carry, take all dosage form easily.We's odd-numbered day crude drug amount has 83g, and the extractum of extraction is prepared into tablet, capsule and all can makes dose of patient bigger about 20g, as: with No. 0 capsule, 0.5 gram/grain, 40 of day dosing.Cause loss of effective components too big as undue making with extra care, affect the treatment; Granule preparation technology is simpler relatively, carries, takes all more convenient, more easily taken by the patient, and determined curative effect, therefore select the dosage form of granule as this side.
The selection of (two) granulation condition
1. the character of medicated powder
The gained extract powder is even, fine and smooth after the extracting solution spray drying, water content is low, dissolubility is fabulous, but because specific surface area is very big, thereby the easy moisture absorption, viscosity is strong, and easily adhesion is agglomerating, so its flowability, hygroscopicity are studied, the results are shown in Table 16.
The mensuration of angle of repose: to estimate the flowability of medicated powder angle of repose, when it is generally acknowledged that angle of repose is less than 30 ℃, the powder good fluidity, flowability is bad during greater than 40 ℃.Adopt the fixed funnel method, with the series connection of 3 funnels and be fixed in 4cm place on the graph paper of horizontal positioned, next hopper outlet polishes, carefully pour into medicated powder in the bell mouth of going up most along hopper walls, till the medicated powder cone tip that forms on the graph paper touches funnel, measure the diameter (measuring repeatedly 5 times) of cone bottom by graph paper, calculate angle of repose: tg α=H/R.
The percentile mensuration of moisture absorption: have the exsiccator that fills the sodium chloride supersaturated solution to put into 25 ℃ constant incubator constant temperature 24h, this moment, its inner relative humidity was 75%.Put into the sample of thick about 2mm in the weighing botle bottom of constant weight, accurately weighing is placed in the exsiccator (bottle cap is opened), and 25 ℃ of constant temperature are preserved, and the timing weighing is calculated as follows the moisture absorption percentage rate.
Table 16 medicated powder flowability, hygroscopicity result
The medicated powder flowability is bad as known from Table 16, and stronger hygroscopicity is arranged.
2. the selection of excipient
Because the medicated powder flowability is bad, and stronger hygroscopicity arranged, pre-test result shows: directly granulate relatively more difficult if do not add any adjuvant, therefore select granule to use the molding adjuvant always: dextrin, lactose, starch, fix other granulation condition, with the primary particle yield is that index carries out preferably the results are shown in Table 17.
Particulate preparation: get 10: 1 extract powder and excipient; mixing is crossed sieve No. 4, with an amount of 90% ethanol system soft material; cross sieve No. 2; oscillating granulator is granulated, and 60 ℃ of hot air dryings are crossed the sieve granulate No. 1; sift out fine powder with No. 4; granule continues at 60 ℃, and to be dried to water content be 1.56%, to cross No. 1 sieve but the granule that can not cross No. 4 sieves is qualified granule, is calculated as follows the granule yield:
Granule yield=(qualified particle weight)/(extractum grain weight+adjuvant is heavy) * 100%
The kind of table 17 excipient and granule yield
It is better to make excipient with dextrin and lactose as known from Table 17, but the price of lactose is higher 4 times than dextrin, in order to save production cost, so select for use dextrin to make excipient.
3. the investigation of dextrin addition
Add can reduce behind an amount of dextrin draw moist, make molding easy, but from production cost with take the dosage aspect and consider, the adjuvant amount should be few more good more, on the basis of pre-test result, be index and the dextrin addition investigated (granule yield computational methods are the same) with the primary particle yield, the results are shown in Table 18.
Table 18 dextrin consumption is investigated table as a result
It is easier to find out that from table 18 dextrin and dried cream ratio are equal to or greater than molding in 1: 10.
4. concentration of alcohol determines
The ethanol of debita spissitudo is made wetting agent, helps preparing soft material and granule, crosses to exceed the low granulation that all is difficult to, and simultaneously, suitable ethanol also helps particle drying, and it is suitable to make in grain hardness, and color and luster is even.Therefore fixing above-mentioned preferred condition is that index is determined concentration of alcohol (mensuration of angle of repose, granule yield, the percentile assay method of moisture absorption are the same) with angle of repose, granule yield, hygroscopicity.On probation 80%, 85%, 90%, 95% ethanol is crossed 16 mesh sieves and is granulated, and granule after the drying, with 10 orders, 60 mesh sieve granulate, makes granule at temperature drying below 60 ℃, the results are shown in Table 19.
The investigation table of table 19 concentration of alcohol
As can be seen from Table 19, angle of repose＞40 of dry powder ° before granulating through behind the alcohol granulation, are reduced to about 36 ° angle of repose, show that flowability improves; 48h moisture absorption percentage rate is never granulated and preceding 15% is reduced to about 6% after the granulation, and moisture resistance is obviously strengthened.Relatively Different concentrations of alcohol is granulated, and finds for a short time with 95% alcohol granulation viscosity, and fine powder is many; 85%, 80% alcohol granulation, viscosity is too big, and material stops up screen cloth easily when causing granulating, and the granule yield is lower.And use 90% alcohol granulation, viscosity is moderate, uniform particles, and granule yield height.Therefore determine to use 90% alcohol granulation.
Comprehensive above-mentioned investigation result; determine that preparations shaping technology is: got dry powder and dextrin 10: 1, and stirred, cross sieve No. 4; with an amount of 90% ethanol system soft material; cross sieve No. 2, oscillating granulator is granulated, 60 ℃ of hot air dryings; cross the sieve granulate No. 1; sift out fine powder with No. 4, granule continues at 60 ℃ of dryings, promptly.
(3) drying condition
The granule of making has certain viscosity, and baking temperature is higher than 60 ℃ of then easy surface knot lump, and temperature-rise period wants slowly, though as being elevated to rapidly that 60 ℃ of surfaces have been done and inside is fully dry.When producing greatly, industry adopt airpillow-dry to overcome the above problems.
(4) single dose determines
Because being the clinical prescription development, this product forms, every day, crude drug dosage was 83g, Radix Salviae Miltiorrhizae, Radix Et Rhizoma Rhei be 20g altogether, is about 19% with yield of extract behind the ethanol extraction, gets dry extract and is about 3.8g, medicinal residues behind Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei ethanol extraction and other liquid medicine extracted extract yield are about 20%, get dry extract and be about 16g, consider the practical situation in the large-scale production process, make granule 20g altogether so determine to add an amount of excipient, take each 10g every day 2 times.
[pilot scale research]
In order to verify and improve the process rationality of laboratory research, and guarantee that preparation (method for making) reaches the operability of production, we feed intake by 10 times of amounts of preparation prescription amount, the extraction of using pilot plant concentrates unit, optimum process condition to laboratory research has carried out three batches of scale-ups, the concrete operations step is as follows, and the main production equipments catalog sees Table 20, and experimental result sees Table 21.
Table 20, main production equipments catalog
Table 21 pilot scale technological production norm table
| Lot number | 031105 | 031106 | 031107 |
| Inventory (kg) | 41.5 | 41.5 | 41.5 |
| Extractum must be measured (kg) | 8.7 | 9.0 | 8.5 |
| Supplementary product consumption (kg) | 0.87 | 0.90 | 0.85 |
| Granule must be measured (kg) | 9.55 | 9.90 | 9.35 |
| Finished product must be measured (bag) | 949 | 978 | 930 |
| Finished product yield (%) | 94.9 | 97.8 | 93.0 |
| The finished product TANSHINONES rate of transform (%) | 64.1 | 65.5 | 66.0 |
| Moisture | 3.9％ | 4.5％ | 4.2％ |
| Content uniformity | Qualified | Qualified | Qualified |
| Discrimination test | Positive | Positive | Positive |
The above results shows that technology condition is preferably reasonable, and device therefor is adapted to the production of this product, and the every technical parameter of product is stable, and is up-to-standard.This process stabilizing is feasible.
[adjuvant source and quality standard]
Dextrin: this product should meet pertinent regulations under two 1038 pages of dextrin items of Chinese Pharmacopoeia (2000 editions).
[the pharmacological data of Chinese medicine preparation of the present invention]
One. Chinese medicine preparation of the present invention is to the influence of rat acute gouty arthritis
Get 60 of SD female rats, body weight 200-220g is divided into normal control group, model control group, colchicine group, the high, medium and low dosage group of health emaciation due to emotional upset granule at random.The oral Chinese medicine preparation 1.7g/kg of the present invention of rat, 3.4g/kg, 6.8g/kg, and with colchicine 0.48g/kg as positive control, successive administration 7 days, after the last administration 1 hour, rats by intraperitoneal injection pentobarbital sodium (40mg/kg) anesthesia, with No. 5 entry needles proceeds posterolateral outside being tried the right ankle joint of rat is point of puncture, injects 50ml uric acid sodium solution (20mg/ μ l) in the ankle joint chamber to articular cavity.The normal control group is injected 50 μ lPB5, continue administration two days, survey rat swollen joint expansibility respectively at 4,12,24 hours employing toes volume determination methods after the modeling, take off after 72 hours and tried the joint, adopt ELISA double-antibody sandwich euzymelinked immunosorbent assay (ELISA) to measure IL-1 β, PEG
2Content.The result shows: three dosage groups of Chinese medicine preparation of the present invention and colchicine group and model control group relatively have obvious suppression effect (PC＜0.01) to the rat arthroncus.Chinese medicine preparation height of the present invention, middle dosage can make acute gouty arthritis animal pattern local joint inflammatory factor IL-1 β and PEG
2All descend.Wherein IL-1 β (pg/ml) model group is 95.7 ± 22.1; Colchicine is 60.2 ± 25.6; The high, medium and low dosage of Chinese medicine preparation of the present invention is respectively 52.3 ± 29.2,57.4 ± 26.5,72.7 ± 32.5; PEG
2(μ g/ml); Model group is 20.6 ± 7.2, and colchicine is 9.3 ± 6.9, and the high, medium and low dosage of Chinese medicine preparation of the present invention is respectively 8.6 ± 3.7,7.2 ± 3.2,15.7 ± 6.3.Above-mentioned experimental result as seen, the oral Chinese medicine preparation of the present invention of rat has the reduction effect to acute gouty arthritis class model joint of animal local inflammation factor IL-1 β.By reducing the level of IL-1 β, can reduce the expression of its induction of vascular endothelial cell, reduce macrophage etc., synthetic IL-6, IL-8 and TNF-a, thus reduce inflammation reaction.
Two. Chinese medicine preparation of the present invention is to the influence of rat urate excretion
Get 50 of SD rats, body weight 240-260g, female, measure uric acid concentration in the blood earlier,
Again by blood uric acid concentration at random equilibrium be divided into normal control group, benzbromarone (0.02g/kg) positive controls, the high, medium and low dosage group of Chinese medicine preparation of the present invention (being respectively 1.7g/kg, 3.4g/kg and 6.8g/kg).Every day gastric infusion once, continuous 7 days.The 45min rat is anaesthetized with pentobarbital sodium after the administration in the 7th day.As vein constant speed (0.1ml/min) input 5% mannitol normal saline, to keep certain urine amount is arranged in the rat 6h, collect urine simultaneously.Collect after the administration blood of 6h after the urine in the 1-6h and administration respectively.With uric acid, the creatine concentration in biochemistry analyzer mensuration blood plasma and the urine, and blood uric acid reduces percentage rate after calculating administration.Uric acid output result: to blood uric acid reduction rate (%); The normal control group is 10.02 ± 10.37; The benzbromarone group is 50.37 ± 21.56; The high, medium and low dosage of Chinese medicine preparation of the present invention is respectively 42.60 ± 15.32,33.70 ± 17.21,13.26 ± 9.31.The result shows that benzbromarone, Chinese medicine preparation height of the present invention, middle dosage all can obviously improve blood uric acid and reduce percentage rate, and Chinese medicine preparation low dose group of the present invention does not have significant difference.To rat urine uric acid output (μ mol/min): the normal control group is 0.018 ± 0.050, the benzbromarone group is 0.028 ± 0.013, the high, medium and low dosage group of Chinese medicine preparation of the present invention is respectively 0.026 ± 0.012,0.024 ± 0.014,0.020 ± 0.018.The result as seen, benzbromarone and Chinese medicine preparation height of the present invention, middle dosage all can improve the urine uric acid output.
Three. the analgesic activity of Chinese medicine preparation of the present invention
3.1 influence to mice hot plate method pain valve
Adopt hot plate method to survey mice pain valve, choose that qualified (50 of the female Kunming mouses of 5s＜pain valve＜30s), body weight 20-22g is divided into 5 groups at random.Normal control group, colchicine group (0.1g/kg), the high, medium and low dosage group of Chinese medicine preparation of the present invention (9.84g/kg, 4.92g/kg and 2.46g/kg), every day gastric infusion once, totally seven days.After the last administration, 1h and 2h survey mice pain valve (second).Normal group pain valve is respectively 13.2 ± 3.7 and 16.9 ± 4.2 as a result, colchicine is respectively 34.6 ± 10.2 and 39.6 ± 12.3, the high, medium and low dosage of Chinese medicine preparation of the present invention is respectively 34.6 ± 10.2 and 43.7 ± 11.5,29.6 ± 8.3 and 32.7 ± 7.6,26.4 ± 6.2 and 29.1 ± 7.3, and the result shows the pain valve that all can obviously improve mice with four administration groups of normal group comparison.
3.2 Dichlorodiphenyl Acetate causes the influence of pain mice
Get 50 of Kunming mouses, male and female half and half, body weight 20-22g is divided into 5 groups at random, normal control group, colchicine group (0.1g/kg), the high, medium and low dosage group of Chinese medicine preparation of the present invention (9.84g/kg, 4.92g/kg, 2.46g/kg).Every day gastric infusion once, continuous seven days.45min after the last administration, every Mus lumbar injection 0.7% acetic acid 0.2ml/ are only.Observe mouse writhing number of times in the 20min.The normal control group is 36.2 ± 11.4 times as a result, colchicine group 16.7 ± 9.9 times, the high, medium and low dosage group of Chinese medicine preparation of the present invention is respectively 17.6 ± 10.2,22.4 ± 11.5,25.6 ± 10.8 times, the result as seen, four administration groups all can obviously reduce acetic acid and cause pain mouse writhing number of times, have significant analgesia role.
Four. brief summary and discussion
Acute gouty arthritis is because the inflammatory reaction that the urate crystal deposition causes.The adult rat single ankle joint local injection uric acid sodium 50 μ l (20m g/ml) that adopt make animal model show the early stage acute attack of gout more in the modern pharmacodynamic study, the typical cytopathic process that occurs the peak rapidly and alleviate subsequently.More fully simulated human acute gouty arthritis.This test adopts above-mentioned Research of Animal Model for Study result to show: Chinese medicine preparation of the present invention has stronger inhibitory action to rat acute gouty arthroncus due to the uric acid sodium, to local joint inflammatory factor IL-1 β and PEG
2The reduction effect is all arranged.Can significantly promote simultaneously the drainage of uric acid in the rat body, and have significant analgesia role.
Claims (7)
1. Chinese medicine preparation for the treatment of gout, it is characterized in that, the raw material that comprises following weight portion, 5～40 parts of Rhizoma Smilacis Glabraes, 3～30 parts of Rhizoma Alismatis, 5～25 parts of Radix Salviae Miltiorrhizaes, 10～30 parts of Rhizoma Dioscoreae Septemlobaes, 1～20 part of Fructus Corni, 1～20 part of Radix Et Rhizoma Rhei, 5～40 parts of Celastrus orbiculatus Thunb.s, 1～20 part of Fructus Aurantii.
2. the Chinese medicine preparation of treatment gout according to claim 1 is characterized in that, comprises the raw material of following weight portion, 8 parts of Rhizoma Smilacis Glabraes, 6 parts of Rhizoma Alismatis, 6 parts of Radix Salviae Miltiorrhizaes, 6 parts of Rhizoma Dioscoreae Septemlobaes, 2 parts of Fructus Corni, 2 parts of Radix Et Rhizoma Rhei, 6 parts of Celastrus orbiculatus Thunb.s, 2 parts of Fructus Aurantiis.
3. the Chinese medicine preparation of treatment gout according to claim 1 and 2 is characterized in that, the dosage form of this Chinese medicine preparation comprises oral liquid, tablet, capsule and granule.
4. prepare a kind of method for the treatment of the Chinese medicine preparation of gout as claimed in claim 1, it is characterized in that, concrete preparation process is as follows:
1) according to the composition of raw materials proportioning, get Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei of recipe quantity, add 5～7 times of amount 60%～80% ethanol extractions 1～2 hour for the first time, filter; Medicinal residues add 2～5 times of amount 60%～80% ethanol extractions 0.5～1.5 hour again, filter, and filtrate merges, and the relative density that is evaporated to 60 ℃ of heat surveys is 1.05～1.10, and is standby;
2) get all the other 6 flavor medical materials, add Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei medicinal residues after with alcohol extraction, add 8～12 times of water gagings for the first time and extracted 1～2 hour, filter; Add for the second time 6～10 times of water gagings extractions and extracted medical material in 0.5～1.5 hour, filter, filtrate merges, and the relative density that is evaporated to 60 ℃ of heat surveys is 1.05～1.10, and is standby;
3) merge above-mentioned two kinds of concentrated solutions, spray drying, the control inlet temperature is 200～230 ℃, spray speed is 1500～3500ml/h, goes into tower blast 3.0～3.5kg, gets medicine dry powder.
5. a kind of preparation method for the treatment of the Chinese medicine preparation of gout according to claim 4 is characterized in that, concrete preparation process is as follows:
1) according to the composition of raw materials proportioning, get Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei of recipe quantity, add 7 times of amount 80% ethanol extractions 2 hours for the first time, filter; Medicinal residues add 5 times of amount 80% ethanol extractions 0.5 hour again, filter, and filtrate merges, and the relative density that is evaporated to 60 ℃ of heat surveys is 1.05～1.10, and is standby;
2) get all the other 6 flavor medical materials, add Radix Salviae Miltiorrhizae, the Radix Et Rhizoma Rhei medicinal residues after with alcohol extraction, add 12 times of water gagings for the first time and extracted 2 hours, filter; Add for the second time 10 times of water gagings extractions and extracted medical material in 1.5 hours, filter, filtrate merges, and the relative density that is evaporated to 60 ℃ of heat surveys is 1.05～1.10, and is standby;
3) merge above-mentioned two kinds of concentrated solutions, spray drying, the control inlet temperature is 220 ℃, spray speed is 3500ml/h, goes into tower blast 3.0～3.5kg, gets medicine dry powder.
6. according to claim 4 or 5 described a kind of preparation methoies for the treatment of the Chinese medicine preparation of gout, it is characterized in that, after making medicine dry powder, with the dry powder of 10 weight portions and the dextrin mix homogeneously of 0.25～2 weight portion, 80%～98% alcohol granulation, drying, granulate, packing gets granular preparation.
7. the application in preparation treatment gouty arthritis or antihyperuricemic disease drug as claim 1 or 2 or 3 described Chinese medicine preparation.
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| CN105412270A (en) * | 2014-09-22 | 2016-03-23 | 天津巨兴科技发展有限公司 | Chinese herbal medicine compound preparation for treating gout |
| CN105497701A (en) * | 2016-01-16 | 2016-04-20 | 杜志政 | Natural medicine for treating gout diseases and preparation method thereof |
| CN110141629A (en) * | 2019-05-27 | 2019-08-20 | 河南中医药大学 | A kind of Chinese medicine for treating hyperuricemia |
| CN111973719A (en) * | 2020-09-17 | 2020-11-24 | 楚雄彝族自治州中医医院 | Yi medicine for gout remission stage |
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